The Effects of Dapagliflozin on HDL Particles Subtypes and Reverse Cholesterol Transport in Type 2 Diabetic Patients
Information source: University of Padova
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Type 2 Diabetes
Intervention: Dapagliflozin (Drug)
Phase: Phase 4
Status: Not yet recruiting
Sponsored by: University of Padova Overall contact: Davide Grisafi, PharmD, Phone: 00390498218165, Email: davide.grisafi@sanita.padova.it
Summary
In Phase 2b/3 clinical trials, Dapagliflozin has been shown to raise HDL cholesterol levels
by about 4 mg/dl (1 mmol/l), which is generally considered a clinically-meaningful change.
As this HDL cholesterol increase is carried out with concomitant improvement in
glucotoxicity and body weight reduction, it is possible that treatment with Dapagliflozin
also improves HDL function. This is important because clinical, epidemiological and
experimental studies indicate that HDL function may be more important than HDL cholesterol
levels in determining the protective cardiovascular effects of HDL particles. In addition,
knowing the effects of Dapagliflozin on HDL function can help interpreting the increase in
HDL cholesterol levels observed in Dapagliflozin-treated patients. Finally, discovery of
extra-glycemic effects of Dapagliflozin will shed new light on the potential benefits of
therapy with Dapagliflozin and SGLT2i in general. So far, no study evaluated the effects of
Dapagliflozin (or other SGLT2i) on HDL function.
The investigators hypothesize that Dapagliflozin, in addition to raising HDL cholesterol
levels, also increases HDL functionality, measured as reverse cholesterol transport and
anti-oxidant capacity, in patients with T2DM
Clinical Details
Official title: The Effects of Dapagliflozin on HDL Particles Subtypes and Reverse Cholesterol Transport in Type 2 Diabetic Patients. A 12 Weeks Randomized Placebo-controlled Phase IV Study
Study design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Primary outcome: Change from baseline in reverse cholesterol transport, measured as cholesterol efflux capacity of patient's plasma
Secondary outcome: Changes from baseline in HDL cholesterol levelsChanges from baseline in the distribution in HDL subclasses Changes from baseline in HDL antioxidant activity Changes from baseline in CETP activity Safety as measured by monitoring of adverse events
Detailed description:
Sodium glucose co-transport-2 (SGLT-2) inhibitors (SGLT-2i), a new class of glucose-lowering
agents, reduce tubular glucose reabsorption, thus lowering blood glucose without stimulating
insulin release. SGLT-2i have been found to be effective in improving glucose control in
type 2 diabetic patients at any disease stage, and also when added to insulin in type 1
diabetic patients. In addition to the glycosuric effect, SGLT-2i reduce body weight and
blood pressure and determine an increase in HDL cholesterol levels. HDL mediate reverse
cholesterol transport, by extracting cholesterol from peripheral tissues and cells and
vehiculating it to the liver. This function, which is regulated that by enzyme cholesteryl
esther transfer protein (CETP), is considered a fundamental mechanism of protection from
accumulation of cholesterol in the vasculature and a physiologic barrier against
atherosclerosis development and protection. The sophisticated method to precisely assess
reverse cholesterol transport in vitro are available in our research lab. Although it has
been reported that therapy with SGLT-2i raise HDL concentrations by about 4 mg/dL (0. 1
mmol/L), the mechanisms remains unclear and it is important to assess whether or not this
quantitative increase is coupled to functional improvement in reverse cholesterol transport.
In fact, previous studies on HDL-raising therapies have clarified that not all HDL particles
and functional and HDL cholesterol levels might not be representative of the reverse
cholesterol transport processes. In addition to cholesterol transport, normal HDL particles
also have anti-oxidant and anti-inflammatory properties, that are important to translate HDL
cholesterol levels into cardiovascular protection. Several HDL subclasses have been
identified, having different composition and anti-atherosclerotic properties.
Dapagliflozin (Bristol-Myers Squibb Company [BMS]-512148) is a highly potent, selective, and
reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), the major transporter
responsible for renal glucose reabsorption. Dapagliflozin lowers plasma glucose by
inhibiting the renal reabsorption of glucose and by promoting its urinary excretion. A
tablet formulation of dapagliflozin for oral administration has been approved in over 40
countries including the European Union (EU) and the United States (US) and is under review
in numerous countries around the world. Dapagliflozin is approved by AIFA with determination
number 909/2013 dated 16/10/2013, and marketing authorization number 042494070/E. In the
Phase 2b and 3 program, dapagliflozin has been studied as monotherapy and in combination
with metformin, pioglitazone, glimepiride, sitagliptin, and insulin. As of 15-Nov-2012 (date
of most recent pooled analysis), a total of 9,412 subjects with T2DM were treated in 16
Phase 3, double-blind, controlled clinical studies conducted to evaluate the safety and
efficacy of dapagliflozin; 5,952 subjects in these studies were treated with dapagliflozin
for up to 80 weeks. The Phase 2b and 3 program established that dapagliflozin is effective
in reducing HbA1c in a broad range of subjects regardless of disease progression/duration or
concomitant use of antidiabetic therapies. Improvements in glycemic control were seen when
dapagliflozin was given as monotherapy; as add-on combination therapy to sitagliptin or
metformin, to sulfonylurea (glimepiride), to thiazolidinedione (pioglitazone), or to insulin
(± oral antidiabetic drugs [OADs]); or as initial combination therapy with metformin.
HDL levels and function. Observational studies provide overwhelming evidence that a low
high-density lipoprotein (HDL)-cholesterol level increases the risk of coronary events, both
in healthy subjects and in patients with coronary heart disease. Based on in vitro
experiments, several mechanistic explanations for the atheroprotective function of HDL have
been suggested. The HDL functions currently most widely held to account for the
antiatherogenic effect include participation in reverse cholesterol transport, protection
against endothelial dysfunction, and inhibition of oxidative stress. Yet, several recent
pharmacological and genetic studies have failed to demonstrate that increased plasma levels
of HDL-C resulted in decreased cardiovascular disease risk, giving rise to a controversy
regarding whether plasma levels of HDL-C reflect HDL function, or that HDL is even as
protective as assumed. The evidence from preclinical and clinical studies shows that HDL can
promote the regression of atherosclerosis when the levels of functional particles are
increased from endogenous or exogenous sources. The data show that regression results from a
combination of reduced plaque lipid and macrophage contents, as well as from a reduction in
its inflammatory state. Although more research will be needed regarding basic mechanisms and
to establish that these changes translate clinically to reduced cardiovascular disease
events, that HDL can regress plaques suggests that the recent trial failures do not
eliminate HDL from consideration as an atheroprotective agent but rather emphasizes the
important distinction between HDL function and plasma levels of HDL-C. While HDL from
healthy subjects can directly stimulate endothelial cell production of nitric oxide and
anti-inflammatory, anti-apoptotic, and anti-thrombotic effects as well as endothelial repair
processes, growing evidence suggests that the vascular effects of HDL can be highly
heterogeneous and vasoprotective properties of HDL are altered in patients with coronary
disease. In fact, HDL has been shown to undergo a loss of function in several
pathophysiological states, as in the acute phase response, obesity and chronic inflammatory
diseases. Some of these diseases were also shown to be associated with increased risk for
cardiovascular disease. One such disease that is associated with HDL dysfunction and
accelerated atherosclerosis is diabetes mellitus, a disease in which the HDL particle
undergoes diverse structural modifications that result in significant changes in its
function, such as glycation and oxidation.
In Phase 2b/3 clinical trials, Dapagliflozin has been shown to raise HDL cholesterol levels
by about 4 mg/dl (1 mmol/l), which is generally considered a clinically-meaningful change.
As this HDL cholesterol increase is carried out with concomitant improvement in
glucotoxicity and body weight reduction, it is possible that treatment with Dapagliflozin
also improves HDL function. This is important because clinical, epidemiological and
experimental studies indicate that HDL function may be more important than HDL cholesterol
levels in determining the protective cardiovascular effects of HDL particles. In addition,
knowing the effects of Dapagliflozin on HDL function can help interpreting the increase in
HDL cholesterol levels observed in Dapagliflozin-treated patients. Finally, discovery of
extra-glycemic effects of Dapagliflozin will shed new light on the potential benefits of
therapy with Dapagliflozin and SGLT2i in general. So far, no study evaluated the effects of
Dapagliflozin (or other SGLT2i) on HDL function. We hypothesize that Dapagliflozin, in
addition to raising HDL cholesterol levels, also increases HDL functionality, measured as
reverse cholesterol transport and anti-oxidant capacity, in patients with T2DM.
This will be a randomized, placebo controlled, parallel group study in 36 type 2 diabetic
patients to assess the effects of Dapagliflozin on HDL levels and function.
The general objective of the project is to detect a significant differences in the changes
versus baseline of the patients' HDL cholesterol efflux capacity, HDL levels, HDL
subclasses, HDL anti-oxidant activity, CETP activity, serum/plasma cytokines and adipokines
(IL-6, IL-8, PAI-1, TNF-α, visfatin, resistin, adiponectin, leptin) in patients randomized
to dapagliflozin compared to those randomized to placebo
Eligibility
Minimum age: 18 Years.
Maximum age: 75 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Provision of informed consent prior to any study specific procedures
- Female and male subjects aged 18-75 years
- Type 2 diabetes on oral agents +/- insulin
- Diabetes duration >6 months
- HbA1c 7. 0-10. 0%
Exclusion Criteria:
- Acute illness or infection
- Recent (within 1 month) surgery, trauma, cardiovascular event
- Recent (within 3 months) variation of statin therapy/dose
- Therapy with HDL-modifying drugs, such as fibrates, omega-3 fatty acids, and niacin
- Alcoholism
- Very high baseline HDL levels (>90 mg/dL)
- Previous history of recurrent (≥2 episodes) urinary tract infections or genital
infections (a single remote episode not to be considered an exclusion criterion)
- History of hypotension, episodes of volume depletion / dehydration.
- Chronic renal failure (eGFR<60 ml/min/1. 73 mq)
- Chronic liver disease (SGOT or GPT >2-fold ULN, or cirrhosis)
- Elevated hematocrit (>50% for men or >45% for women)
- Heart failure, NYHA classes III-IV
- Hypersensitivity to Dapagliflozin or its excipients
- Treatment with pioglitazone or GLP-1 receptor agonists
- Women with childbearing potential
Locations and Contacts
Davide Grisafi, PharmD, Phone: 00390498218165, Email: davide.grisafi@sanita.padova.it
Division of Metabolic Diseases, University Hospital of Padova, Padova 35128, Italy; Not yet recruiting Angelo Avogaro, MD PhD, Phone: 00390498212178, Email: angelo.avogaro@unipd.it Gian Paolo Fadini, MD PhD, Phone: 00390498214318, Email: gianpaolo.fadini@unipd.it
Additional Information
Starting date: February 2015
Last updated: December 29, 2014
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